Transient expression of FRNK reveals stage-specific requirement for focal adhesion kinase activity in cardiac growth.
Transient expression of FRNK reveals stage-specific requirement for focal adhesion kinase activity in cardiac growth.
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DOI：
10.1161/circresaha.109.195941
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发表时间：
2009-05-22
影响因子：
20.1
通讯作者：
Taylor JM
中科院分区：
文献类型：
--
作者：
DiMichele LA;Hakim ZS;Sayers RL;Rojas M;Schwartz RJ;Mack CP;Taylor JM
粘着斑激酶（FAK）被整合素和生长因子强烈激活，对胚胎发育至关重要。我们以前表明，C端的FAK是作为一个单独的蛋白质称为FAK相关的非激酶（FRNK）在平滑肌细胞选择性的方式和FRNK的功能，以缓冲FAK依赖的信号。我们现在发现FRNK在新生儿心肌中也瞬时表达，峰值水平发生在出生后5至7天，就在细胞周期退出之前。使用新的小鼠模型，我们证明，心脏选择性表达FRNK（导致抑制FAK）从胚胎第10.5天开始导致严重的心室致密化不全缺陷与心肌细胞增殖减少。值得注意的是，出生后几乎相同水平的FRNK表达耐受良好，不影响生存力或合成代谢心脏生长。尽管如此，FRNK在成人心脏中的表达确实减弱了主动脉缩窄后的病理性心脏肥大，证实并扩展了我们先前的数据，即这种代偿反应在FAK缺失的心脏中是钝化的。我们在培养的新生心肌细胞中的机制研究表明，FRNK表达诱导p38/p27 kip依赖的细胞周期退出，并减弱细胞外信号调节激酶依赖的肥大性生长。这些发现表明，FRNK在新生儿心脏中的动态表达可能起到促进心肌细胞在特别富含生长因子和生长促进细胞外基质的环境中静止的作用。
Focal adhesion kinase (FAK) is strongly activated by integrins and growth factors and is essential for embryonic development. We previously showed that the C terminus of FAK is expressed as a separate protein termed FAK-related nonkinase (FRNK) in a smooth muscle cell–selective fashion and that FRNK functions to buffer FAK-dependent signals. We now show that FRNK is also transiently expressed in the neonatal myocardium, with peak levels occurring 5 to 7 days postnatal, just before cell cycle withdrawal. Using novel mouse models, we demonstrate that cardiac-selective expression of FRNK (leading to inhibition of FAK) starting at embryonic day 10.5 leads to a severe ventricular noncompaction defect associated with reduced cardiomyocyte proliferation. Remarkably, postnatal expression of nearly identical levels of FRNK is well tolerated and does not affect viability or anabolic cardiac growth. Nonetheless, FRNK expression in the adult heart does attenuate pathological cardiac hypertrophy following aortic banding, confirming and extending our previous data that this compensatory response is blunted in FAK null hearts. Our mechanistic studies in cultured neonatal cardiomyocytes reveal that FRNK expression induces p38/p27kip-dependent cell cycle withdrawal and attenuates extracellular signal-regulated kinase–dependent hypertrophic growth. These findings indicate that dynamic expression of FRNK in the neonatal heart may function to promote cardiomyocyte quiescence in an environment that is particularly rich in growth factors and growth promoting extracellular matrices.